EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells.
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ABSTRACT:
SUBMITTER: Stairiker CJ
PROVIDER: S-EPMC8683156 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB-dependent antitumor response in hB7-H3-overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1+Tim-3+ "terminally differentiated" subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB-expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3-positive cancers as monotherapy and combination therapy with PD-1 blockade.
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Project description:To improve the potential treatment strategies of incurable renal cell carcinoma (RCC), which is highly resistant to chemotherapy and radiotherapy, the present study established a combination therapy with immunostimulatory factor (ISTF) and anti-4-1BB monoclonal antibodies (mAbs) to augment the antitumor response in a murine RCC model. ISTF isolated from Actinobacillus actinomycetemcomitans stimulates macrophages, dendritic cells and B cells to produce IL-6, TNF-α, nitric oxide and major histocompatibility complex class II expression. 4-1BB (CD137) is expressed in activated immune cells, including activated T cells, and is a promising target for cancer immunotherapy. The administration of anti-4-1BB mAbs promoted antitumor immunity via enhancing CD11c+CD8+ T cells. The CD11c+CD8+ T cells were characterized by high killing activity and IFN-γ-producing ability, representing a phenotype of active effector cytotoxic T lymphocytes. The present study showed that combination therapy with ISTF and anti-4-1BB mAbs promoted partial tumor regression with established RCC, but monotherapy with ISTF or anti-4-1BB mAbs did not. These effects were speculated to be caused by the increase in CD11c+CD8+ T cells in the spleen and tumor, and IFN-γ production. These insights into the effector mechanisms of the combination of ISTF and anti-4-1BB mAbs may be useful for targeting incurable RCC.
| S-EPMC8674882 | biostudies-literature
Project description:To better understand how innate and adaptive immune responses interact with each other, we combined 4-1BB T cell costimulation with specific adjuvants to determine whether these treatments would influence specific T cell expansion and function in vivo. In the presence of 4-1BB ligation and Toll-like receptor 3 (TLR)3 and/or TLR4 triggering, CD8 T cell clonal expansion and survival was augmented profoundly. Specific T cells primed in vivo with TLR ligands responded normally to in vitro recall stimulus, but, surprisingly, copriming with 4-1BB costimulation significantly impaired the recall response even though many more specific effector T cells were rescued in vivo. Here, we demonstrate that the rescued CD8 T cells suppressed CD4 T cell proliferation via a type beta transforming growth factor-dependent mechanism. Thus, 4-1BB and TLR ligands induce survival of specific effector CD8 T cells with suppressive recall potential, which may explain the dual role that 4-1BB activation plays in mediating tumor clearance and prevention of autoimmune disease.
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Project description:4-1BB (CD137) is a strong enhancer of the proliferation of CD8+ T cells. Since these cells require increased production of energy and biomass to support their proliferation, we hypothesized that 4-1BB signaling activated glucose and fatty acid metabolism. We found that treatment with agonistic anti-4-1BB mAb promoted the proliferation of CD8+ T cells in vitro, increasing their size and granularity. Studies with a glycolysis inhibitor and a fatty acid oxidation inhibitor revealed that CD8+ T cell proliferation required both glucose and fatty acid metabolism. Anti-4-1BB treatment increased glucose transporter 1 expression and activated the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK)-acetyl-CoA carboxylase (ACC) signaling pathway, which may be responsible for activating the metabolism of glucose and fatty acids. We also examined whether blocking glucose or fatty acid metabolism affected cell cycle progression and the anti-apoptotic effect of 4-1BB signaling. The increase of anti-apoptotic factors and cyclins in response to anti-4-1BB treatment was completely prevented by treating CD8+ T cells with the fatty acid oxidation inhibitor, etomoxir, but not with the glycolysis inhibitor, 2-deoxy-D-glucose. We conclude that anti-4-1BB treatment activates glucose and fatty acid metabolism thus supporting the increased demand for energy and biomass, and that fatty acid metabolism plays a crucial role in enhancing the cell cycle progression of anti-CD3-activated CD8+ T cells in vitro and the anti-apoptotic effects of 4-1BB signaling on these cells.
| S-EPMC5596242 | biostudies-literature
Project description:Simian immunodeficiency virus (SIV) insert-expressing, 68-1 rhesus cytomegalovirus (RhCMV/SIV) vectors elicit major histocompatibility complex E (MHC-E)- and MHC-II-restricted, SIV-specific CD8+ T cell responses, but the basis of these unconventional responses and their contribution to demonstrated vaccine efficacy against SIV challenge in the rhesus monkeys (RMs) have not been characterized. We show that these unconventional responses resulted from a chance genetic rearrangement in 68-1 RhCMV that abrogated the function of eight distinct immunomodulatory gene products encoded in two RhCMV genomic regions (Rh157.5/Rh157.4 and Rh158-161), revealing three patterns of unconventional response inhibition. Differential repair of these genes with either RhCMV-derived or orthologous human CMV (HCMV)-derived sequences (UL128/UL130; UL146/UL147) leads to either of two distinct CD8+ T cell response types-MHC-Ia-restricted only or a mix of MHC-II- and MHC-Ia-restricted CD8+ T cells. Response magnitude and functional differentiation are similar to RhCMV 68-1, but neither alternative response type mediated protection against SIV challenge. These findings implicate MHC-E-restricted CD8+ T cell responses as mediators of anti-SIV efficacy and indicate that translation of RhCMV/SIV vector efficacy to humans will likely require deletion of all genes that inhibit these responses from the HCMV/HIV vector.
| S-EPMC8244349 | biostudies-literature
Project description:Although cancer immunotherapy is effective against hematological malignancies, it is less effective against solid tumors due in part to significant metabolic challenges present in the tumor microenvironment (TME), where infiltrated CD8+ T cells face fierce competition with cancer cells for limited nutrients. Strong metabolic suppression in the TME is often associated with impaired T cell recruitment to the tumor site and hyporesponsive effector function via T cell exhaustion. Increasing evidence suggests that mitochondria play a key role in CD8+ T cell activation, effector function, and persistence in tumors. In this study, we showed that there was an increase in overall mitochondrial function, including mitochondrial mass and membrane potential, during both mouse and human CD8+ T cell activation. CD8+ T cell mitochondrial membrane potential was closely correlated with granzyme B and IFN-γ production, demonstrating the significance of mitochondria in effector T cell function. Additionally, activated CD8+ T cells that migrate on ICAM-1 and CXCL12 consumed significantly more oxygen than stationary CD8+ T cells. Inhibition of mitochondrial respiration decreased the velocity of CD8+ T cell migration, indicating the importance of mitochondrial metabolism in CD8+ T cell migration. Remote optical stimulation of CD8+ T cells that express our newly developed "OptoMito-On" successfully enhanced mitochondrial ATP production and improved overall CD8+ T cell migration and effector function. Our study provides new insight into the effect of the mitochondrial membrane potential on CD8+ T cell effector function and demonstrates the development of a novel optogenetic technique to remotely control T cell metabolism and effector function at the target tumor site with outstanding specificity and temporospatial resolution.
| S-EPMC8209468 | biostudies-literature
Project description:Enhancing long-term persistence while simultaneously potentiating the effector response of CD8+ T cells has been a long-standing goal in immunology to produce better vaccines and adoptive cell therapy products. NR4A3 is a transcription factor of the orphan nuclear receptor family. While it is rapidly and transiently expressed following T cell activation, its role in the early stages of T cell response is unknown. We show that NR4A3-deficient murine CD8+ T cells differentiate preferentially into memory precursor and central memory cells, but also produce more cytokines. This is explained by an early influence of NR4A3 deficiency on the memory transcriptional program and on accessibility of chromatin regions with motifs for bZIP transcription factors, which impacts the transcription of Fos/Jun target genes. Our results reveal a unique and early role for NR4A3 in programming CD8+ T cell differentiation and function. Manipulating NR4A3 activity may represent a promising strategy to improve vaccination and T cell therapy.
| S-EPMC7533658 | biostudies-literature
Project description:BackgroundIncreasing infiltration of CD8+ T cells within tumor tissue predicts a better prognosis and is essential for response to checkpoint blocking therapy. Furthermore, current clinical protocols use unfractioned T cell populations as the starting point for transduction of chimeric antigen receptors (CARs)-modified T cells, but the optimal T cell subtype of CAR-modified T cells remains unclear. Thus, accurately identifying a group of cytotoxic T lymphocytes with high antitumor efficacy is imperative. Inspired by the theory of yin and yang, we explored a subset of CD8+ T cell in cancer with the same phenotypic characteristics as highly activated inflammatory T cells in autoimmune diseases.MethodsCombination of single-cell RNA sequencing, general transcriptome sequencing data and multiparametric cytometric techniques allowed us to map CXCR6 expression on specific cell type and tissue. We applied Cxcr6-/- mice, immune checkpoint therapies and bone marrow chimeras to identify the function of CXCR6+CD8+ T cells. Transgenic Cxcr6-/- OT-I mice were employed to explore the functional role of CXCR6 in antigen-specific antitumor response.ResultsWe identified that CXCR6 was exclusively expressed on intratumoral CD8+ T cell. CXCR6+CD8+ T cells were more immunocompetent, and chimeras with specific deficiency on CD8+ T cells showed weaker antitumor activity. In addition, Cxcr6-/- mice could not respond to anti-PD-1 treatment effectively. High tumor expression of CXCR6 was not mainly caused by ligand-receptor chemotaxis of CXCL16/CXCR6 but induced by tumor tissue self. Induced CXCR6+CD8+ T cells possessed tumor antigen specificity and could enhance the effect of anti-PD-1 blockade to retard tumor progression.ConclusionsThis study may contribute to the rational design of combined immunotherapy. Alternatively, CXCR6 may be used as a biomarker for effective CD8+ T cell state before adoptive cell therapy, providing a basis for tumor immunotherapy.
| S-EPMC8407215 | biostudies-literature
Project description:Background & aimsBesides secreting pro-inflammatory cytokines, chemokines and effector molecules, effector CD8+ T cells that arise upon acute infection with certain viruses have been shown to produce the regulatory cytokine interleukin (IL)-10 and, therefore, contain immunopathology. Whether the same occurs during acute hepatitis B virus (HBV) infection and role that IL-10 might play in liver disease is currently unknown.MethodsMouse models of acute HBV pathogenesis, as well as chimpanzees and patients acutely infected with HBV, were used to analyse the role of CD8+ T cell-derived IL-10 in liver immunopathology.ResultsMouse HBV-specific effector CD8+ T cells produce significant amounts of IL-10 upon in vivo antigen encounter. This is corroborated by longitudinal data in a chimpanzee acutely infected with HBV, where serum IL-10 was readily detectable and correlated with intrahepatic CD8+ T cell infiltration and liver disease severity. Unexpectedly, mouse and human CD8+ T cell-derived IL-10 was found to act in an autocrine/paracrine fashion to enhance IL-2 responsiveness, thus preventing antigen-induced HBV-specific effector CD8+ T cell apoptosis. Accordingly, the use of mouse models of HBV pathogenesis revealed that the IL-10 produced by effector CD8+ T cells promoted their own intrahepatic survival and, thus supported, rather than suppressed liver immunopathology.ConclusionEffector CD8+ T cell-derived IL-10 enhances acute liver immunopathology. Altogether, these results extend our understanding of the cell- and tissue-specific role that IL-10 exerts in immune regulation. Lay summary: Interleukin-10 is mostly regarded as an immunosuppressive cytokine. We show here that HBV-specific CD8+ T cells produce IL-10 upon antigen recognition and that this cytokine enhances CD8+ T cell survival. As such, IL-10 paradoxically promotes rather than suppresses liver disease.
| S-EPMC7127652 | biostudies-literature
Project description:For successful immunotherapy for cancer, it is important to understand the immunological status of tumor antigen-specific CD8+ T cells in the tumor microenvironment during tumor progression. In this study, we monitored the behavior of B16OVA-Luc cells in mice immunized with a model tumor antigen ovalbumin (OVA). Using bioluminescence imaging, we identified the time series of OVA-specific CD8+ T-cell responses during tumor progression: initial progression, immune control, and the escape phase. As a result of analyzing the status of tumor antigen-specific CD8+ cells in those 3 different phases, we found that the expression of NKG2D defines tumor-reacting effector CD8+ T cells. NKG2D may control the fate and TOX expression of tumor-reacting CD8+ T cells, considering that NKG2D blockade in OVA-vaccinated mice delayed the growth of the B16OVA-Luc2 tumor and increased the presence of tumor-infiltrating OVA-specific CD8+ T cells.
| S-EPMC8409295 | biostudies-literature